Optic neuritis is an inflammatory demyelinating disease of the optic nerve that occurs idiopathically or in association with the central nervous system (CNS) demyelinating disease multiple sclerosis (MS). Up to 60% of patients with optic neuritis develop some permanent visual loss including decreased acuity, color vision, contrast sensitivity and/or visual field loss. Axonal damage and loss of neurons occurs in optic neuritis and MS, including loss of retinal ganglion cells (RGCs), and this neuronal loss leads to permanent neurological dysfunction. Identifying novel therapies that prevent neuronal loss following optic neuritis therefore has tremendous potential for preventing permanent visual loss. Neuroprotective therapies that work in optic neuritis also have potential to prevent loss of retina neurons in other eye diseases, and loss of other CNS neurons in MS as well, if the therapy targets a common mechanism of neuronal cell damage. Studies over the first four to five years of this grant demonstrated that resveratrol, a naturally- occurring polyphenol, and other related compounds that share an ability to activate the SIRT1 deacetylase, provide significant neuroprotective effects for RGCs. SIRT1 activity is a critical part of the mechanism of resveratrol mediated prevention of RGC loss and preservation of visual function. Furthermore, results suggest that suppression of the inflammatory component of this disease does not occur, and therefore is not a significant part of the mechanism of action of resveratrol. Resveratrol treatment also reduces accumulation of reactive oxygen species in optic nerves, decreasing oxidative stress that contributes to RGC loss in experimental optic neuritis. Preliminary data suggests one mechanism mediating this effect involves SIRT1 deacetylation of PGC1?, a coactivator of transcription factors that lead to increased mitochondrial biogenesis, with associated increased expression of mitochondrial enzymes involved in reduction of reactive oxygen species, including superoxide dismutase 2 (SOD2). We hypothesize that resveratrol treatment will provide added benefits to optic neuritis eyes without reducing the ability of immunomodulatory therapies to suppress inflammation and demyelination, by promoting RGC survival and preservation of RGC function; and one mechanism of this neuroprotective effect involves resveratrol mediated activation of SIRT1 to deacetylate PGC1? and reduce oxidative stress through increased mitochondrial biogenesis. To test this hypothesis we propose two specific aims: 1) Evaluate synergistic effects and safety of combined treatment with resveratrol and anti-inflammatory therapies in experimental optic neuritis; and 2) Determine the role of PGC1? in modulating mitochondrial function and inducing SOD2 to reduce oxidative stress as mechanisms of resveratrol mediated neuroprotection of RGCs.